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Biomedical subjects

P Lichtner

Publications and source records attributed to P Lichtner.

At least 19 recordsLinked to original sources
PubMed2006

Comprehensive association analysis of the NOS2A gene with Parkinson disease.

Inducible nitric oxide synthase (NOS2A) may be involved in the oxidative stress pathology of Parkinson disease (PD). Two previous studies reported an association of a single nucleotide polymorphism (rs1060826) with PD. A replication study of 340 German patients and 680 controls showed no significant association between 12 genotyped polymorphisms and PD. NOS2A is therefore not a major susceptibility locus in our relatively young sample population.

Alleles↗
PubMed2006

Idiopathic generalized epilepsy phenotypes associated with different EFHC1 mutations.

We sequenced 61 patients with various idiopathic generalized epilepsy (IGE) syndromes for mutations in the EFHC1 gene. We detected three novel heterozygous missense mutations (I174V, C259Y, A394S) and one possibly pathogenic variant in the 3' UTR (2014t>c). The mutation I174V was also detected in 1 of 372 screened patients with temporal lobe epilepsy. We conclude that mutations in the EFHC1 gene may underlie different types of epilepsy syndromes.

3' Untranslated Regions↗
PubMed2006

Mutations in the CLCN2 gene are a rare cause of idiopathic generalized epilepsy syndromes.

Mutations in the chloride channel gene CLCN2 have been reported in families with generalized and focal epilepsy syndromes. To evaluate the contribution of mutations in the CLCN2 gene to the etiology of epilepsies in our population, we screened 96 patients with different epilepsy syndromes and a putative genetic background. No definite mutations were found in our study population. We conclude that mutations in the CLCN2 gene are only a rare cause of idiopathic generalized epilepsy.

CLC-2 Chloride Channels↗
PubMed2006

The sepiapterin reductase gene region reveals association in the PARK3 locus: analysis of familial and sporadic Parkinson's disease in European populations.

BACKGROUND: Parkinson's disease is a genetically complex disease with mixed mode of inheritance. Recently, a haplotype across the sepiapterin reductase (SPR) gene, which is located in the PARK3 linkage region, was shown to modulate age of onset of Parkinson's disease in sibships from North America. OBJECTIVE: To make a thorough assessment of the SPR gene region in sporadic Parkinson's disease. METHODS: A linkage study in 122 European sibship families with five microsatellite and 17 single nucleotide polymorphism (SNP) markers in and around the SPR gene region, and an association analysis in 340 sporadic cases of Parkinson's disease and 680 control subjects from Germany with 40 SNPs. Linkage was evaluated by non-parametric linkage scores and genotypic or haplotype association was tested by regression analysis, assuming different risk effect models. RESULTS: Significant LOD scores between 2 and 3 were obtained at the two SPR-flanking markers D2S2110 and D2S1394 and seven SNP markers around the SPR gene. We found the previously reported promoter SNP rs1876487 also significantly associated with age of onset in our sib pair families (p-value 0.02). One strong linkage disequilibrium (LD) block of 45 kb including the entire SPR gene was observed. Within this LD block all 14 inter-correlated SNPs were significantly associated with Parkinson's disease affection status (p-value 0.004). CONCLUSIONS: DNA polymorphisms in a highly intercorrelated LD block, which includes the SPR gene, appear to be associated with both sporadic and familial Parkinson's disease. This confirms a previous study showing that SPR potentially modulates the onset of or risk for Parkinson's disease.

Age of Onset↗
PubMed2002

Expression and mutation analysis of BRUNOL3, a candidate gene for heart and thymus developmental defects associated with partial monosomy 10p.

Partial monosomy 10p is a rare chromosomal aberration. Patients often show symptoms of the DiGeorge/velocardiofacial syndrome spectrum. The phenotype is the result of haploinsufficiency of at least two regions on 10p, the HDR1 region associated with hypoparathyroidism, sensorineural deafness, and renal defects (HDR syndrome) and the more proximal region DGCR2 responsible for heart defects and thymus hypoplasia/aplasia. While GATA3 was identified as the disease causing gene for HDR syndrome, no genes have been identified thus far for the symptoms associated with DGCR2 haploinsufficiency. We constructed a deletion map of partial monosomy 10p patients and narrowed the critical region DGCR2 to about 300 kb. The genomic draft sequence of this region contains only one known gene, BRUNOL3 ( NAPOR, CUGBP2, ETR3). In situ hybridization of human embryos and fetuses revealed as well as in other tissues a strong expression of BRUNOL3 in thymus during different developmental stages. BRUNOL3 appears to be an important factor for thymus development and is therefore a candidate gene for the thymus hypoplasia/aplasia seen in partial monosomy 10p patients. We did not find BRUNOL3 mutations in 92 DiGeorge syndrome-like patients without chromosomal deletions and in 8 parents with congenital heart defect children.

Adult↗
PubMed2002

Reduced amplification efficiency of KIAA0027/MLC1 alleles: implications for the molecular diagnosis of megalencephalic leukoencephalopathy with subcortical cysts.

Autosomal recessive megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare childhood-onset spongiform leukodystrophy with macrocephaly and slowly progressive deterioration of motor functions. Mutations in KIAA0027/MLC1 have recently been found associated with MLC, and a high degree of allelic heterogeneity has been observed. In addition, initial reports suggested that a rare variant in exon 11 (L309M) is involved in the etiology of schizophrenia, but recent studies have brought forward compelling arguments that genetic variants of MLC1 are not associated with schizophrenia. Using DHPLC-analysis, reproduction of previous findings on L309M revealed homoduplex resolution patterns among individuals, who had been described to be heterozygous for the variant, which was further confirmed by sequencing the respective PCR products. Cumulative effects of high GC content, secondary folding structures due to incomplete intronic tandem-repeats, and a complicated insertion polymorphism at the 3-end of exon 11 may be the cause of preferential amplification of specific alleles of exon 11. Consistent amplification was obtained only when we employed exonic primers directly adjacent to the L309M variant. For mutational screening, we propose a two-step test: (1) testing for the 33 bp insertion polymorphism of exon 11, and (2) amplification of the exon using different primer sets depending on the presence or absence of the insertion.

Alleles↗
PubMed2001

Nonlocal Kardar-Parisi-Zhang equation to model interface growth.

The dynamics of the growth of interfaces in the presence of noise and when the normal velocity is constant, in the weakly nonlinear limit, are described by the Kardar-Parisi-Zhang (KPZ) equation. In many applications, however, the growth is controlled by nonlocal transport, which is not contained in the original KPZ equation. For these problems we are proposing an extension of the KPZ model, where the nonlocal contribution is expressed through a Hilbert transform and can act to either stabilize or destabilize the interface. The model is illustrated with a specific example from reactive infiltration. The properties of the solution of the resulting equation are studied in one spatial dimension in the linear and the nonlinear limits, for both stable and unstable growth. We find that the early-time behavior has a power-law scaling similar to that of the KPZ equation. However, in the case of stable growth, the scaling of the saturation width is logarithmic, which differs from the power law in the KPZ equation. This dependence reflects the stabilizing effect of nonlocal transport. In the unstable case, we obtain results similar to those of Olami et al. [Phys. Rev. E 55, 2649 (1997)].

Journal Article↗
PubMed2001

Cloning of the human MCCA and MCCB genes and mutations therein reveal the molecular cause of 3-methylcrotonyl-CoA: carboxylase deficiency.

3-Methylcrotonyl-CoA: carboxylase (EC 6.4.1.4; MCC) deficiency is an inborn error of the leucine degradation pathway (MIM *210200) characterized by increased urinary excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine. The clinical phenotypes are highly variable ranging from asymptomatic to profound metabolic acidosis and death in infancy. Sequence similarity with Glycine max and Arabidopsis thaliana genes encoding the two subunits of MCC permitted us to clone the cDNAs encoding the alpha- and beta-subunits of human MCC. The 2580 bp MCCA cDNA encodes the 725 amino acid biotin-containing alpha-subunit. The MCCA gene is located on chromosome 3q26-q28 and consists of 19 exons. The 2304 bp MCCB cDNA encodes the non-biotin-containing beta-subunit of 563 amino acids. The MCCB gene is located on chromosome 5q13 and consists of 17 exons. We have sequenced both genes in four patients with isolated biotin-unresponsive deficiency of MCC. In two of them we found mutations in the MCCA gene. Compound heterozygosity for a missense mutation (S535F) and a nonsense mutation (V694X) were identified in one patient. One heterozygous mutation (S535F) was found in another patient. The remaining two patients had mutations in the MCCB gene. One consanguineous patient was homozygous for a missense mutation (R268T). In the other we identified a missense mutation in one allele (E99Q) and allelic loss of the other. Mutations were correlated with an almost total lack of enzyme activity in fibroblasts. These data provide evidence that human MCC deficiency is caused by mutations in either the MCCA or MCCB gene.

Carbon-Carbon Ligases↗
PubMed2001

Complete form of X-linked congenital stationary night blindness: refined mapping and evidence of genetic homogeneity.

A number of distinct, partly non-overlapping genetic loci have been reported for the complete type of X-linked congenital stationary night blindness (CSNB1), suggesting genetic heterogeneity. In order to refine the localization of the CSNB1 gene and to demonstrate genetic homogeneity, linkage analysis was performed in two large CSNB1 families. Clinical features consistent with the diagnosis of CSNB1 were documented in five patients from a German seven-generation kindred by full ophthalmological examination including psychophysical and electroretinographical testing. Haplotype analysis in 30 members of the large German family was performed with 38 polymorphic markers predominantly covering the critical region. Linkage analyses defined a locus for CSNB1 with flanking markers DXS8042 and DXS228, refining the interval to 2.5 cM in Xp11.4. In addition, two-point linkage analysis was carried out using the MLINK computer program. In agreement with meiotic breakpoints, lod scores of 3.0 and greater were obtained for markers located to the proximal site of the former 5 cM CSNB consensus interval. A large Dutch CSNB1 family was re-evaluated with markers from the Xp11.4 region, and supports the CSNB1 minimal interval found in the German family. Together with previous results from three unrelated families from Sweden, Sardinia and Great Britain, our results provide evidence of genetic homogeneity in the disorder. Subsequent mutation analyses in CSNB1 patients revealed no pathogenic sequence alterations in DFFRX and CASK genes, but retain candidates for other diseases mapping to that region.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed2000

GATA3 haplo-insufficiency causes human HDR syndrome.

Terminal deletions of chromosome 10p result in a DiGeorge-like phenotype that includes hypoparathyroidism, heart defects, immune deficiency, deafness and renal malformations. Studies in patients with 10p deletions have defined two non-overlapping regions that contribute to this complex phenotype. These are the DiGeorge critical region II (refs 1, 2), which is located on 10p13-14, and the region for the hypoparathyroidism, sensorineural deafness, renal anomaly (HDR) syndrome (Mendelian Inheritance in Man number 146255), which is located more telomeric (10p14-10pter). We have performed deletion-mapping studies in two HDR patients, and here we define a critical 200-kilobase region which contains the GATA3 gene. This gene belongs to a family of zinc-finger transcription factors that are involved in vertebrate embryonic development. Investigation for GATA3 mutations in three other HDR probands identified one nonsense mutation and two intragenic deletions that predicted a loss of function, as confirmed by absence of DNA binding by the mutant GATA3 protein. These results show that GATA3 is essential in the embryonic development of the parathyroids, auditory system and kidneys, and indicate that other GATA family members may be involved in the aetiology of human malformations.

Amino Acid Sequence↗
PubMed2000

An HDR (hypoparathyroidism, deafness, renal dysplasia) syndrome locus maps distal to the DiGeorge syndrome region on 10p13/14.

Partial monosomy 10p is a rare chromosomal condition and a significant proportion of patients show features of DiGeorge syndrome (DGS) and velocardiofacial syndrome (VCFS). A critical haploinsufficiency region for DGS/VCFS was defined on 10p (DGCR2). We performed molecular deletion analysis of two further patients with partial monosomy 10p, who showed hypoparathyroidism, deafness, and renal dysplasia or renal insufficiency, but no cardiac defect, cleft palate, or reduced T cell levels. Previously, the combination of hypoparathyroidism, deafness, and renal dysplasia has been proposed to represent a specific syndrome (MIM 146255) under the acronym HDR. In addition to the two patients in this report, at least four published cases with partial monosomy 10p show the triad of HDR and 14 other patients present with at least two of the three features. We therefore conclude that HDR syndrome can be associated with partial monosomy 10p. Based on molecular deletion analysis and the clinical data, we suggest that the DGS/VCFS phenotype associated with 10p deletion can be considered as a contiguous gene syndrome owing to haploinsufficiency of two different regions. Hemizygosity of the proximal region, designated DGCR2, can cause cardiac defect and T cell deficiency. Hemizygosity of the distal region, designated HDR1, can cause hypoparathyroidism and in addition sensorineuronal deafness and renal dysplasia/insufficiency or a subset of this triad.

Adult↗
PubMed1999

Genetic and structural characterization of the human mitochondrial inner membrane translocase.

Translocation of nuclear-encoded mitochondrial preproteins is mediated by translocases in the outer and inner membranes. In the yeast Saccharomyces cerevisiae, translocation of preproteins into the matrix requires the membrane proteins Tim23, Tim17 and Tim44, which drive translocation in cooperation with mtHsp70 and its co-chaperone Mge1p. We have cloned and functionally analyzed the human homologues of Tim17, Tim23 and Tim44. In contrast to yeast, two TIM17 genes were found to be expressed in humans. TIM44, TIM23 and TIM17a genes were mapped to chromosomes 19p13.2-p13.3, 10q11. 21-q11.23 and 1q32. The TIM17b gene mapped to Xp11.23, near the fusion point where an autosomal region was proposed to have been added to the "ancient" part of the X chromosome about 80-130 MY ago. The primary sequences of the two proteins, hTim17a and hTim17b, are essentially identical, significant differences being restricted to their C termini. They are ubiquitously expressed in fetal and adult tissues, and both show expression levels comparable to that of hTim23. Biochemical characterization of the human Tim components revealed that hTim44 is localized in the matrix and, in contrast to yeast, only loosely associated with the inner membrane. hTim23 is organized into two distinct complexes in the inner membrane, one containing hTim17a and one containing hTim17b. Both TIM complexes display a native molecular mass of 110 kDa. We suggest that the structural organization of TIM23.17 preprotein translocases is conserved from low to high eukaryotes.

Adult↗
PubMed1999

Full length cDNA cloning, promoter sequence, and genomic organization of the human adrenoleukodystrophy related (ALDR) gene functionally redundant to the gene responsible for X-linked adrenoleukodystrophy.

X-linked adrenoleukodystrophy (X-ALD) is a functional defect of the ALD Protein (ALDP), an ABC half-transporter localized in the peroxisomal membrane. It is characterized by defective, very long chain fatty acid (VLCFA) beta-oxidation, resulting in progressive cerebral demyelination. Since individual mutations in the ALD gene may result in a variety of clinical phenotypes, the existence of modifying genetic factors has been proposed. The adrenoleukodystrophy related protein (ALDRP), a close homolog of ALDP, has been shown to complement the defect of VLCFA oxidation if transfected into X-ALD cells or chemically induced in ALDP-deficient mice. Chemical ALDRP induction holds a potential for a novel therapeutic strategy. We report here the exclusively peroxisomal localization of human ALDRP, the full length cDNA, the transcriptional start, and 2.4 kb of the putative promoter region DNA sequence. The human ALDR gene extends over 33 kb on chromosome 12q12 and consists of 10 exons. The gene structure is highly similar to the ALD gene, indicating a recent divergence from a common ancestor. The putative human promoter sequence contains a novel motif conserved in peroxisomal ABC transporters in the mouse. Our data will enable sequence analysis in X-ALD patients to determine a possible role of ALDRP as a modifier and provide tools for the study of therapeutic ALDRP induction.

ATP Binding Cassette Transporter, Subfamily D↗
PubMed1999

De novo deletion (14)(q11.2q13) including PAX9: clinical and molecular findings.

A 3 year old boy with a de novo deletion (14)(q11.2q13) of paternal origin encompassing the region from D14S264 to D14S70 is described. The patient presented with severe psychomotor retardation, bilateral cleft lip/palate, bilateral colobomas of the optic nerves and retinas, agenesis of the corpus callosum, pes calcaneovarus, reduced oesophageal peristalsis, and swallowing difficulties. This is the first reported case of PAX9 hemizygosity in humans. Haploinsufficiency of the PAX9 gene might be expected to cause some of the developmental defects and the dysphagia. Another haploinsufficiency candidate gene, the bZIP transcription factor gene NRL, which is specifically expressed in neuronal cells and the eye during embryogenesis, was excluded from the deletion interval.

Abnormalities, Multiple↗
PubMed1998

Genomic organization and chromosomal localization of the human peroxisomal membrane protein-1-like protein (PXMP1-L) gene encoding a peroxisomal ABC transporter.

The cDNA of the peroxisomal membrane protein-1-like protein (PXMP1-L, synonyms: PMP69, P70R), a novel peroxisomal ATP binding cassette transporter of yet unknown function, has recently been cloned. The best known peroxisomal member of this protein family is the adrenoleukodystrophy protein, defects of which are the underlying cause of X-linked adrenoleukodystrophy (X-ALD). Here we describe the complete exon-intron structure (19 exons and 18 introns covering 16.0 kb) of the human PXMP1-L gene, transcript variants, the localization on chromosome 14q24 by cytogenetic analysis and sequencing of the putative promoter region. PXMP1-L has been proposed to play a role as a modifier in determining the phenotypic variations observed in X-ALD. The data presented will enable sequence analysis of the PXMP1-L gene in X-ALD patients and facilitate the analysis of PXMP1-L function.

ATP-Binding Cassette Transporters↗
PubMed1996

Craniosynostosis suggestive of Saethre-Chotzen syndrome: clinical description of a large kindred and exclusion of candidate regions on 7p.

We describe the clinical manifestations of an autosomal dominant form of craniosynostosis in a large family with eight affected relatives. Unilateral or bilateral coronal synostosis, low frontal hair line, strabismus, ptosis, and partial cutaneous syndactyly of fingers and toes are findings suggestive of the diagnosis of Saethre-Chotzen syndrome. The disease locus was excluded from the two adjacent Saethre-Chotzen candidate regions on 7p by linkage analysis with markers D7S664 and D7S507. This indicates heterogeneity of Saethre-Chotzen syndrome with a locus outside the candidate regions on 7p.

Acrocephalosyndactylia↗